瑞士巴赛尔大学的Christoph Hess研究团队发现，SDHA基因突变后的功能获得通过KEAP1-Nrf2信号通路参与炎性线粒体逆行信号转导。2019年9月16日，国际知名学术期刊《自然—免疫学》在线发表了这一成果。

研究人员前瞻性地筛选发现细胞外酸化率可作为糖酵解的量度方式，而氧消耗率可作为主要抗体缺乏患者B细胞线粒体呼吸的量度方式。研究人员在具有持续多克隆B淋巴细胞增多症（PPBL）的三名研究参与者中检测到最高耗氧率值。外显子组测序鉴定了所有三名PPBL患者中编码琥珀酸脱氢酶亚基A的SDHA基因中的种系突变。SDHA功能获得导致PPBL B细胞中富马酸盐的积累，其使用KEAP1-Nrf2系统来驱动编码炎性细胞因子基因的转录。在单个患者试验中，阻断体内细胞因子白细胞介素6的活性可防止全身性炎症并改善临床疾病。

总体而言，这项研究已将病理性线粒体逆行信号鉴定为主要抗体缺乏的疾病调节者。

研究人员介绍，筛选免疫细胞的代谢活动是否有助于分子病理的发现仍然未知。

附：英文原文

Title: SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1–Nrf2

Author: Anne-Valrie Burgener, Glenn R. Bantug, Benedikt J. Meyer, Rebecca Higgins, Adhideb Ghosh, Olivier Bignucolo, Eric H. Ma, Jordan Loeliger, Gunhild Unterstab, Marco Geigges, Rebekah Steiner, Michel Enamorado, Robert Ivanek, Danielle Hunziker, Alexander Schmidt, Bojana Mller-Durovic, Jasmin Grhlert, Raja Epple, Sarah Dimeloe, Jonas Ltscher, Ursula Sauder, Monika Ebnther, Bettina Burger, Ingmar Heijnen, Sarai Martnez-Cano, Nathan Cantoni, Rolf Brcker, Christian R. Kahlert, David Sancho, Russell G. Jones, Alexander Navarini, Mike Recher, Christoph Hess

Issue&Volume: 2019-09-16

Abstract: 

Whether screening the metabolic activity of immune cells facilitates discovery of molecular pathology remains unknown. Here we prospectively screened the extracellular acidification rate as a measure of glycolysis and the oxygen consumption rate as a measure of mitochondrial respiration in B cells from patients with primary antibody deficiency. The highest oxygen consumption rate values were detected in three study participants with persistent polyclonal B cell lymphocytosis (PPBL). Exome sequencing identified germline mutations in SDHA, which encodes succinate dehydrogenase subunit A, in all three patients with PPBL. SDHA gain-of-function led to an accumulation of fumarate in PPBL B cells, which engaged the KEAP1–Nrf2 system to drive the transcription of genes encoding inflammatory cytokines. In a single patient trial, blocking the activity of the cytokine interleukin-6 in vivo prevented systemic inflammation and ameliorated clinical disease. Overall, our study has identified pathological mitochondrial retrograde signaling as a disease modifier in primary antibody deficiency.

DOI: 10.1038/s41590-019-0482-2

Source:https://www.nature.com/articles/s41590-019-0482-2